Inflammation Research[JOURNAL]
Sun
200 papers
ABCA8 drives bone loss via disrupting Th17/Treg imbalance: a novel immunometabolic target for osteoporosis.
Yi W, Xu W, Yang T … +7 more , Lyu X, Wang Z, Chen L, Zhang J, Zhong Y, Wang S, Wu B
Inflamm Res · 2026 Jun · PMID 42228211 · Full text
BACKGROUND: Osteoporosis is a metabolic bone disease characterized by reduced bone mass and microarchitectural deterioration, with complex involvement of molecular networks and immune-associated transcriptional dysregula...
BACKGROUND: Osteoporosis is a metabolic bone disease characterized by reduced bone mass and microarchitectural deterioration, with complex involvement of molecular networks and immune-associated transcriptional dysregulation. OBJECTIVE: This study aimed to elucidate the immune-associated regulatory features of ATP-binding cassette subfamily A member 8 (ABCA8) in osteoporosis. METHODS: Differential gene expression analysis was performed using the GSE35958 dataset, and 384 up-regulated genes and 1143 down-regulated genes were identified. Weighted gene co-expression network analysis (WGCNA) and machine learning-based feature selection (LASSO, random forest, and Boruta) were applied to identify key osteoporosis-associated genes. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were conducted to explore immune-associated transcriptional signatures, including Th17- and regulatory T cell (Treg)-related signatures. In vivo validation was conducted in ovariectomized (OVX) rats, with gene modulation experiments evaluating bone phenotypes, osteogenic and osteoclastic markers, and inflammatory cytokine profiles. RESULTS: ABCA8 was significantly upregulated in osteoporotic samples and associated with osteoporosis-related transcriptional features. High ABCA8 expression was associated with altered immune-associated signatures, including Th17- and regulatory T cell (Treg)-related transcriptional features, as revealed by ssGSEA. Pathway analyses further linked ABCA8 expression to immune regulation and inflammatory signaling pathways. In OVX rats, ABCA8 knockdown improved trabecular bone microarchitecture, upregulated osteogenic markers (Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteoprotegerin (OPG)), and downregulated bone resorption markers (receptor activator of nuclear factor κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP)). Conversely, ABCA8 overexpression aggravated bone loss and was accompanied by disruption of the Th17/Treg balance and increased levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17). CONCLUSION: ABCA8 is closely associated with osteoporosis-related immune-associated transcriptional alterations and contributes to disease progression through dysregulation of osteoimmune balance. These findings suggest that ABCA8 may represent a potential immunoregulatory target for therapeutic intervention in osteoporosis.
Stage-dependent interaction between circulating and tissue-resident memory CD4 T cells in recurrent allergic airway inflammation.
Miao Q, Hou X, Xiang L … +1 more , Shi F
Inflamm Res · 2026 Jun · PMID 42228188 · Publisher ↗
Asthma exacerbation remains a major clinical challenge, yet the immunological mechanisms sustaining recurrent airway inflammation are incompletely understood. In particular, how circulating and tissue-resident memory T-c...
Asthma exacerbation remains a major clinical challenge, yet the immunological mechanisms sustaining recurrent airway inflammation are incompletely understood. In particular, how circulating and tissue-resident memory T-cell populations coordinate systemic recall responses and local persistence during disease relapse remains unclear. To address this, a total of 16 patients with acute asthma exacerbations following a thunderstorm-associated pollen surge and 26 with well-controlled asthma during the same period were enrolled, and the memory CD4 T-cell subsets in the peripheral blood were quantifies. In parallel, an Artemisia (Art)-induced murine model of recurrent allergic airway inflammation was established, in which lymphocyte trafficking was pharmacologically inhibited using FTY720 to dissect the respective contributions of tissue-associated and circulating memory T-cell compartments. Children with acute asthma exacerbations exhibited increased frequencies of circulating CCR4CRTH2 Th2-like memory CD4 T cells, which were associated with enhanced type 2 inflammatory markers and impaired lung function. Repeated allergen exposure induced the persistence of lung tissue-resident memory CD4 T cells together with the re-expansion of circulating memory T cells upon recall challenge. Blockade of lymphocyte egress during the primary phase resulted in only modest attenuation of airway inflammation, whereas sustained blockade during both priming and recall phases effectively suppressed airway inflammation and airway hyper-responsiveness. Collectively, these findings reveal a stage-dependent orchestration of tissue-resident and circulating memory T-cell responses in asthma exacerbation, highlighting the necessity of temporally coordinated therapeutic strategies to achieve sustained disease control.
Gngt2 promotes inflammatory dendritic cell programming through an ATG5-NF-κB signaling axis in neutrophilic asthma.
Ji X, He SD, Yang L … +4 more , You X, Wen T, Chen Z, Zhou Y
Inflamm Res · 2026 Jun · PMID 42228185 · Publisher ↗
BACKGROUND AND OBJECTIVE: Type 2 (T2)-low neutrophilic asthma represents a severe asthma endotype characterized by corticosteroid resistance and persistent airway inflammation driven by dendritic cells (DCs)-mediated T h...
BACKGROUND AND OBJECTIVE: Type 2 (T2)-low neutrophilic asthma represents a severe asthma endotype characterized by corticosteroid resistance and persistent airway inflammation driven by dendritic cells (DCs)-mediated T helper (Th)17 responses. Although immunogenic DC programming plays a central role in this process, the intracellular mechanisms that couple inflammatory signaling to DC functional polarization remain poorly understood. This study investigated whether the G protein subunit gamma transducin 2 (Gngt2) regulates autophagy related protein-dependent inflammatory programming in DCs and thereby contributes to Th17-driven neutrophilic airway inflammation. METHODS: Ovalbumin (OVA)-induced eosinophilic asthma and OVA/lipopolysaccharide (LPS)-induced neutrophilic asthma models were established in BALB/c mice to compare endotype-specific inflammatory responses. Gngt2 was silenced in vivo by intratracheal delivery of lentiviral short hairpin RNA. In vitro, bone marrow-derived dendritic cells (BMDCs) were stimulated with OVA or OVA/LPS and then manipulated by Gngt2 knockdown, ATG5 knockdown, or ATG5 overexpression. In selected experiments, the NF-κB nuclear translocation inhibitor JSH-23 was used to assess pathway dependence. BMDCs were co-cultured with naïve CD4 + T cells to evaluate Th17 differentiation. Airway inflammation, cytokine production, autophagy-related protein expression, and NF-κB activation were assessed by histological, immunological, and molecular analyses. RESULTS: Gngt2 expression was selectively upregulated in lung DCs from mice with neutrophilic asthma and was accompanied by a phenotype with altered autophagy related protein, as indicated by reduced ATG5 abundance, decreased microtubule-associated protein 1 light chain 3 beta (LC3B) expression, and a lower LC3B-II/I ratio. In vivo silencing of Gngt2 markedly attenuated neutrophilic airway inflammation and decreased bronchoalveolar lavage fluid (BALF) levels of interleukin (IL)-6, IL-23, and IL-17, without significantly affecting IL-4. In OVA/LPS-stimulated BMDCs, Gngt2 knockdown restored ATG5/LC3B-associated autophagy-related markers, reduced NF-κB p65 phosphorylation, suppressed IL-6 and IL-23 production, and impaired DC-mediated Th17 differentiation. Rescue experiments further demonstrated that ATG5 acted downstream of Gngt2 to regulate NF-κB activation and inflammatory cytokine production, thereby controlling Th17 polarization. CONCLUSION: Our findings identify a previously unrecognized DC-intrinsic Gngt2-ATG5-NF-κB signaling axis that links G protein-coupled receptor (GPCR)- signaling with immune regulation of altered autophagy related protein in neutrophilic asthma. By suppressing ATG5-mediated signaling, Gngt2 promotes NF-κB activation and contributes to Th17-driven neutrophilic airway inflammation. This pathway provides mechanistic insight into DC-driven immune dysregulation in type 2-low asthma and suggests Gngt2 as a potential therapeutic target for neutrophilic asthma.
SYVN1-provoked RASA1 ubiquitination promotes pulmonary inflammation in chronic obstructive pulmonary disease.
Wu JH, Ma YC, Wang YQ … +14 more , Miao HL, Liu MX, Hua DX, Tang MM, Sui TR, Wu ZY, Wang Y, Yang J, Zhao H, Fei J, Zhao XD, Zhang F, Fu L, Cao W
Inflamm Res · 2026 Jun · PMID 42228184 · Publisher ↗
BACKGROUND AND OBJECTIVE: Ras p21 protein activator 1 (RASA1) is mainly located on cytoplasm and can regulate GTPase activity. The goal of this study was to analyze the association between pulmonary RASA1 expression and...
BACKGROUND AND OBJECTIVE: Ras p21 protein activator 1 (RASA1) is mainly located on cytoplasm and can regulate GTPase activity. The goal of this study was to analyze the association between pulmonary RASA1 expression and chronic obstructive pulmonary disease (COPD) and the potential mechanisms. METHODS: COPD patients and age- and sex-matched control subjects were enrolled. In addition, cigarette smoke (CS) evoked-COPD model in mice and cigarette smoke extract (CSE)-exposed BEAS-2B cells were used. RESULTS: Pulmonary RASA1 expression was reduced compared with control subjects and gradually decreased in parallel with the severity of COPD patients. Correlative analysis found pulmonary RASA1 was positively associated with pulmonary function parameters and inversely correlated with inflammatory cytokines among COPD patients. RASA1 protein expression was downregulated in lung tissues of CS-evoked COPD mice and CSE-exposed BEAS-2B cells. RAS/PI3K/Akt signaling was activated in lung tissues of COPD patients and mice, as well as BEAS-2B cells after CSE treatment. There was a negative correlation between SYVN1 and RASA1 in lung tissues of COPD patients. Mechanistically, CSE exposure enhanced RASA1 proteasome degradation through elevating E3 ubiquitin ligase SYVN1. CS exposure facilitated inflammatory cytokines production via activating RAS/PI3K/Akt signaling. Genetic deletion of SYVN1 alleviated CSE-provoked inflammatory response via inhibiting RAS/PI3K/Akt signaling in BEAS-2B cells. CONCLUSION: These data revealed that E3 ubiquitin ligase SYVN1-provoked RASA1 proteasome degradation involves in inflammatory response through activating RAS/PI3K/Akt signaling in the process of COPD.
Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10 expression.
Lv G, Gao Y, Kang Z … +2 more , Liu Y, Zhang L
Inflamm Res · 2026 Jun · PMID 42228175 · Publisher ↗
BACKGROUND: Activated PI3K-delta syndrome (APDS) is a human monogenic primary immunodeficiency disorder caused by mutations in the gene encoding the p110δ catalytic subunit of phosphoinositide 3-kinase, PIK3CD. APDS is c...
BACKGROUND: Activated PI3K-delta syndrome (APDS) is a human monogenic primary immunodeficiency disorder caused by mutations in the gene encoding the p110δ catalytic subunit of phosphoinositide 3-kinase, PIK3CD. APDS is characterized by complex immune phenotypes, including increased serum IgM, susceptibility to encapsulated bacterial respiratory infections, poor vaccine response, and autoimmune disorders. Impaired B cell development and responses, involving an expansion at the transient transitional T1 stage and a strikingly selective expansion of autoreactive marginal zone B cells, may be largely responsible for these phenotypes, although little is known about the precise underlying mechanisms. METHODS: In this study, we used a mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the spleen marginal zone B cell development. RESULTS: Here, we report that hyperactive P110δ leads to an increase in the proportion of spleen marginal zone B cell precursors with enhanced surface ADAM10 levels, as early as the T1 stage of B cell development. Using single-cell RNA sequencing (scRNA-seq), we also identified divergent cell differentiation at the T1 stage. The ADAM10 inhibitor suppresses marginal zone B cells differentiation and also partially reverses the imbalance of transitional T1 and T2 stage. CONCLUSION: These findings inform understanding of the mechanism underlying imbalanced marginal zone B cell development in APDS from a shallow perspective, and provide a preliminary platform for future investigation of strategies to target autoimmune B cells in this disease.
From Tregs to tissue remodelling: FOXP3 and IL-35 in the inflammatory landscape of nasal polyps.
Gokulakannan G, Che Jalil NA, Kadir R … +4 more , Ramli RR, Abdullah B, Lambuk F, Md Shukri N
Inflamm Res · 2026 Jun · PMID 42228169 · Full text
OBJECTIVE: Inflammatory nasal polyps (NPs) are a chronic condition of the nasal mucosa linked with prolonged airway obstruction, frequent infections, and immune dysregulation. While the exact mechanisms underlying NP dev...
OBJECTIVE: Inflammatory nasal polyps (NPs) are a chronic condition of the nasal mucosa linked with prolonged airway obstruction, frequent infections, and immune dysregulation. While the exact mechanisms underlying NP development remain unknown, new research indicates that immune-regulatory pathways are essential. Forkhead box P3 (FOXP3) and Interleukin-35 (IL-35) have attracted much interest. METHODS: In this narrative review, we examine how regulatory T cells (Tregs) release the potent immunosuppressive cytokine IL-35, suppressing effector T cell responses and encouraging Treg proliferation. Studies have shown that IL-35 is essential for preserving immunological homeostasis. FOXP3, a crucial transcription factor necessary for the development and maintenance of developing and maintaining immunological tolerance, controls the development and activity of Tregs. The pathophysiology of NPs is also included in this review, along with pertinent immunological indicators linked to the advancement of the condition. RESULT: The balance between inflammatory and regulatory responses is upset in NP patients due to dysregulation of IL-35 and FOXP3, exacerbating chronic inflammation. Studying how they interact offers novel insight into the pathophysiology of NP and identifies potential curative approaches, such as Treg regulation and IL-35 supplementation. Parallel to this, pharmacological treatments such as corticosteroids and biologics (such as dupilumab) aim to reduce type 2 inflammation. CONCLUSION: FOXP3 and IL-35 play an important role in maintaining immunological homeostasis, and their dysregulation is associated with the persistent inflammation seen in NPs. Relying on these regulatory mechanisms may represent a promising therapeutic direction, although further experimental and clinical validation is required beyond existing anti-inflammatory therapies. Further investigation is necessary to confirm their clinical relevance.
The CLOCK-BMAL1 complex in circadian regulation: structure, mechanisms, and therapeutic targeting.
Kamel EM, Khadrawy SM, Allam AA … +3 more , Ahmed NA, Alkhayl FFA, Lamsabhi AM
Inflamm Res · 2026 May · PMID 42189225 · Publisher ↗
BACKGROUND: The heterodimeric transcription factor CLOCK-BMAL1 functions as the central activator of the mammalian circadian clock. By integrating basic helix-loop-helix (bHLH) and PAS-domain interaction surfaces, it bin...
BACKGROUND: The heterodimeric transcription factor CLOCK-BMAL1 functions as the central activator of the mammalian circadian clock. By integrating basic helix-loop-helix (bHLH) and PAS-domain interaction surfaces, it binds E-box DNA elements and drives rhythmic transcriptional programs that underlie 24-hour physiological and behavioral cycles. OBJECTIVES: This review consolidates recent structural and biochemical insights into CLOCK-BMAL1, outlines the assays used to discover and validate modulators, and evaluates emerging pharmacology-especially effects on amplitude versus period, cell-specific responses, and potential for chronotherapeutic timing. KEY FINDINGS: Recent structural work reveals that CLOCK-BMAL1 is organized through a modular interface architecture that enables multivalent enhancer occupancy and facilitates coactivator recruitment, particularly CBP/p300, supporting robust transcriptional activation. Repression is imposed by Cryptochromes and Period proteins through defined contacts with the CLOCK-BMAL1 PAS-domain core, thereby tuning interaction affinity and timing across the circadian cycle. These mechanistic insights are beginning to translate into chemical strategies, including direct disruption of the CLOCK-BMAL1 interaction, allosteric ligands targeting the BMAL1 PAS-B pocket, and modulation by endogenous cofactors such as heme that can reshape DNA engagement. Across these approaches, pharmacological effects appear to diverge by mechanism, with distinct impacts on amplitude and period and evidence for cellular context-dependence, while the field continues to refine assay modalities that reliably link target engagement to functional circadian outcomes. CONCLUSIONS: Collectively, advances in structure and mechanism position CLOCK-BMAL1 as a druggable protein-protein interaction target and support a rational path toward next-generation circadian modulators. Key challenges remain, including achieving selectivity over related bHLH-PAS paralogs such as NPAS2, resolving cofactor-bound holocomplex states on chromatin, and converting acute modulation into durable physiological benefit. Addressing these gaps should accelerate translation toward therapeutics that can be precisely tuned and timed to align with circadian biology.
PCSK9 orchestrates the antigen presentation-endothelial barrier axis to potentiate immune exclusion in colorectal cancer.
Wang G, Yue Z, Bian Y … +8 more , Su T, Qi H, Zhang Y, Wang X, He W, Liang Z, Yin G, Tang D
Inflamm Res · 2026 May · PMID 42189200 · Publisher ↗
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of MHC-I molecules, thereby weakening CD8⁺ T cell-mediated immune surveillance. However, whether PCSK9 additionally regulates imm...
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of MHC-I molecules, thereby weakening CD8⁺ T cell-mediated immune surveillance. However, whether PCSK9 additionally regulates immune infiltration through the tumor vascular barrier remains unknown. METHODS: This study employed a colorectal cancer (CRC) organoid-T cell coculture system, human umbilical vein endothelial cell (HUVEC) barrier assays, and a patient-derived orthotopic xenograft (PDOX) liver metastasis model. PCSK9 was knocked down to assess its effects on antigen presentation, T cell activation, endothelial integrity, and tumor growth. RESULTS: PCSK9 knockdown significantly upregulated MHC-I expression, enhanced CD8⁺ T cell activation and cytotoxicity, and induced high production of IFN-γ and TNF-α. These cytokines disrupted VE-cadherin-mediated endothelial junctions, reduced transendothelial electrical resistance (TEER), increased vascular permeability, and promoted deep T cell infiltration, ultimately suppressing tumor growth. Consistent in vitro and in vivo findings provided closed-loop validation from molecular to histological levels. CONCLUSIONS: For the first time, this study reveals that PCSK9 establishes a multilevel immunoregulatory axis spanning antigen presentation, T cell activation, and the vascular barrier, driving immune evasion and microenvironmental remodeling in CRC. Inhibition of PCSK9 simultaneously activates antitumor immunity and optimizes the vascular microenvironment, presenting a promising combinatorial therapeutic target against CRC metastasis.
Targeting mTOR with vistusertib attenuates metabolic steatohepatitis and prevents HCC development.
Sharma N, Panneerselvam S, Chandra Y … +1 more , Andugulapati SB
Inflamm Res · 2026 May · PMID 42189199 · Publisher ↗
OBJECTIVE: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder characterised by lipid accumulation, leading to inflammation, hepatocellular injury, varying degrees of fibrosis, and ult...
OBJECTIVE: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder characterised by lipid accumulation, leading to inflammation, hepatocellular injury, varying degrees of fibrosis, and ultimately hepatocellular carcinoma (HCC). Despite recent advances in drug discovery (approval of resmetirom and semaglutide), MASH remains an unmet medical need, highlighting the need for new therapies to halt disease progression and prevent complications such as HCC. This study aimed to investigate the therapeutic effect of the mTORC1/2 inhibitor (vistusertib) against the spectrum of liver disorders. METHODS: Palmitic/oleic acid-treated HepG2, HSC-LX2 cells, LPS-stimulated RAW264.7, HHSECs, and TGF-β-activated HSC-LX2 cells were used to evaluate the therapeutic potential of vistusertib across liver disease models (n = 3). In vivo efficacy against inflammation, fibrosis, and HCC was assessed using streptozotocin (insulin resistance) and high-fat diet-induced (STAM) MASH models (n = 6), with molecular analyses of oxidative stress, fibrotic, and oncogenic markers confirming broad hepatoprotective activity. RESULTS: Vistusertib significantly (p < 0.001) reduced lipid accumulation, LPS-driven inflammation, and TGFβ-induced fibrosis in various in vitro models. It also suppressed cell migration (HepG2), sphere formation, and expression of cancer stem cell markers at low concentrations. In the STAM mouse model (C57BL/6 with streptozotocin and high-fat diet), vistusertib significantly (p < 0.05) decreased hepatic lipid accumulation, de novo lipogenesis, and hepatocellular ballooning. MASH-induced fibrotic markers and collagen deposition were markedly attenuated via mTOR signalling modulation. Importantly, vistusertib reduced tumour nodule formation, suggesting its ability to block MASH progression to HCC, with a confirmed favourable safety profile. CONCLUSION: Our findings identify vistusertib as a promising candidate for MASH, capable of mitigating disease progression and preventing MASH-to-HCC transition, highlighting its potential in managing metabolic liver disorders.
In vivo colonic epithelial cell editing attenuates intestinal inflammation in mice.
Zhang H, Lu H, Zhang S … +5 more , Hu X, Wu Q, Yu Z, Lienanto NK, Zhang J
Inflamm Res · 2026 May · PMID 42154259 · Publisher ↗
The management of inflammatory bowel disease (IBD) remains challenging, primarily due to the insufficient precision and efficacy of existing therapies. Consequently, there is an urgent need to develop novel treatment app...
The management of inflammatory bowel disease (IBD) remains challenging, primarily due to the insufficient precision and efficacy of existing therapies. Consequently, there is an urgent need to develop novel treatment approaches. Here, we developed a therapeutic approach to generate epithelial cells with enhanced efferocytic capacity in vivo by delivering mRNA in lipid nanoparticles (LNPs). We demonstrated that LNPs-mediated delivery of mRNA enables functional editing of epithelial cells in vitro and in vivo, and our findings suggest that enhanced efferocytosis in engineered epithelial cells may contribute to inflammation resolution and restoration of tissue homeostasis. In murine models of colitis, intraperitoneal administration of mRNA-loaded nanoparticles designed to boost efferocytosis markedly attenuated intestinal inflammation and halted disease progression. This strategy provides a proof of concept that epithelial cells can be functionally engineered in situ and represents a promising therapeutic avenue for mitigating inflammatory tissue damage.
Alveolar macrophage-neutrophil crosstalk in acute lung injury: mechanisms, feedback loops, and therapeutic opportunities.
Tao ZA, Li LL, Wang J … +2 more , Niu CY, Zhao ZG
Inflamm Res · 2026 May · PMID 42154058 · Publisher ↗
BACKGROUND: Acute lung injury (ALI) is a life-threatening condition characterized by dysregulated pulmonary inflammation and high mortality rates. Alveolar macrophages and neutrophils are central innate immune cells that...
BACKGROUND: Acute lung injury (ALI) is a life-threatening condition characterized by dysregulated pulmonary inflammation and high mortality rates. Alveolar macrophages and neutrophils are central innate immune cells that orchestrate the inflammatory response in injured lungs. Accumulating evidence indicates that dynamic interactions between these two cell types play a pivotal role in ALI progression; however, the underlying regulatory mechanisms remain insufficiently understood. OBJECTIVE: This review aims to comprehensively analyze themolecular and cellular processes governing the communication between alveolar macrophages and neutrophils in ALI and to discuss emerging therapeutic strategies targeting this cell-cell interaction, with the goal of providing insights into novel biomarkers and therapeutic targets for ALI. METHODS: A comprehensive review of the relevant literature was conducted to summarize the molecular and cellular mechanisms underlyingalveolar macrophage-neutrophil crosstalk in ALI, including cytokine/chemokine signaling, pattern recognition receptor activation, inflammasome pathways, reactive oxygen species-mediated regulation, and neutrophil extracellular trap formation. In addition, therapeutic strategies targeting these interactions were collated and analyzed. RESULTS: Alveolar macrophage-neutrophil communication in ALI is mediatedby multiple pathways, including cytokine and chemokine signaling, pattern recognition receptor activation, inflammasome activation, reactive oxygen species regulation, and neutrophil extracellular trap (NET) formation. Bidirectional feedback loops exist between the two cell types,where they either amplify or limit each other's activities depending on the pathological state, thereby regulating the balance between host defense and tissue damage. Emerging therapeutic strategies targeting this crosstalk, such as the modulation of macrophage inflammatory phenotypes, inhibition of neutrophil recruitment, and prevention of neutrophil extracellular trap formation, show promising translational potential for restoring immune homeostasis in ALI. CONCLUSION: Alveolar macrophage-neutrophil crosstalk constitutes a critical regulatory axisin ALI pathogenesis. Elucidating the mechanisms and feedback networks of this interaction is essential for identifying novel biomarkers and therapeutic targets, which will facilitate the development of more precise and effective immunomodulatory treatments for ALI.
Clinical value of LncRNA PAX8-AS1 as a biomarker for sepsis diagnosis and prognosis and its regulatory mechanism via the miR-34a-5p/HDAC1 axis.
Chen Q, Zhang E, Zhang Y … +2 more , Cheng M, Liu F
Inflamm Res · 2026 May · PMID 42154028 · Publisher ↗
OBJECTIVE: The objective of this research is to evaluate the diagnostic and prognostic significance of lncRNA PAX8-AS1 in sepsis, and explore its function in regulating the inflammatory response at the molecular level. M...
OBJECTIVE: The objective of this research is to evaluate the diagnostic and prognostic significance of lncRNA PAX8-AS1 in sepsis, and explore its function in regulating the inflammatory response at the molecular level. METHODS: This study included 112 sepsis patients and 100 healthy controls. The levels of PAX8-AS1, miR-34a-5p, and target mRNA were quantified using qRT-PCR. Kaplan-Meier analysis was performed to assess 28-day survival. ROC curves were used to evaluate diagnostic efficacy. ELISA measured inflammatory cytokine concentrations. The targeting relationship between PAX8-AS1 and miR-34a-5p, along with the regulatory effect of miR-34a-5p on HDAC1, was confirmed through bioinformatics prediction, dual luciferase reporter assays, and RNA pull-down experiments. RESULTS: PAX8-AS1 expression was significantly higher in sepsis patients, and its expression level positively correlated with the severity of sepsis. PAX8-AS1 demonstrated high diagnostic efficacy for sepsis with an AUC of 0.913. Furthermore, the lower 28-day cumulative survival was observed in patients with high PAX8-AS1 expression relative to their low-expression counterparts. In THP-1 cells, silencing PAX8-AS1 suppressed the inflammatory response triggered by LPS. Mechanistically, PAX8-AS1 sponges miR-34a-5p to exacerbate the inflammatory response. HDAC1 is a direct target of miR-34a-5p. CONCLUSIONS: PAX8-AS1 is highly expressed in sepsis patients and demonstrates diagnostic and prognostic value. By binding to miR-34a-5p to upregulate HDAC1 expression, it promotes inflammatory response.
Epigenetic mechanism of HDAC5 in sepsis-induced acute intestinal injury through KLF4-mediated intestinal epithelial cell ferroptosis.
Zhu JP, Sun MN, Liu SH … +1 more , Du ZA
Inflamm Res · 2026 May · PMID 42154020 · Publisher ↗
OBJECTIVE: This study explores the molecular mechanism of HDAC5 in ferroptosis of intestinal epithelial cells in sepsis-induced acute intestinal injury. METHODS: A mouse model was established by cecal ligation and perfor...
OBJECTIVE: This study explores the molecular mechanism of HDAC5 in ferroptosis of intestinal epithelial cells in sepsis-induced acute intestinal injury. METHODS: A mouse model was established by cecal ligation and perforation (CLP) and an in vitro model of intestinal epithelial cells was induced by lipopolysaccharide (LPS). Immunohistochemistry, RT-qPCR, or Western blot determined the expressions of HDAC5, KLF4, and LncRNA MEG3 in cells. HDAC5 expression was reduced via lentivirus injection and siRNA transfection, followed by evaluation of intestinal tissue injury and cell injury, detection of Fe, ROS, GSH, and MDA levels, as well as detection of ACSL4 and SLC7A11 protein expressions. The permeability was evaluated by detecting the flux of fluorescein isothiocyanate-dextran. ChIP analyzed the enrichment of HDAC5 and H3K27ac on KLF4 promoter. The binding of KLF4 to LncRNA MEG3 promoter was verified by ChIP and dual luciferase assays. RIP and RNA pull down analyzed the binding of LncRNA MEG3 to LSD1. The enrichment of LSD1, H3K4me2, or H3K9me2 on ACSL4 or SLC7A11 promoter was analyzed by ChIP. RESULTS: HDAC5 expression was increased in intestinal tissues of CLP mice and LPS-induced cells, while KLF4 and LncRNA MEG3 expressions were decreased. Low expression of HDAC5 alleviated intestinal tissue injury, enhanced LPS-induced cell viability, and reduced ferroptosis. Mechanistically, HDAC5 inhibited KLF4 expression through deacetylation of H3K27ac, thereby suppressing transcriptional promotion of LncRNA MEG3 by KLF4, reducing recruitment of LSD1, enhancing H3K4me2 on ACSL4 promoter and H3K9me2 enrichment on SLC7A11 promoter, promoting ACSL4 and inhibiting SLC7A11 expression. CONCLUSION: HDAC5 promotes intestinal epithelial cell ferroptosis and exacerbates sepsis-induced acute intestinal injury by inhibiting KLF4/LncRNA MEG3 axis through deacetylation of H3K27ac.
Single-cell and spatial transcriptomics reveal an arachidonic acid-related cellular atlas in lung adenocarcinoma.
Sun C, Zhang Y, Pan Y … +5 more , Xia G, Yang G, Huang C, Li J, Ma P
Inflamm Res · 2026 May · PMID 42151495 · Publisher ↗
PURPOSE: Arachidonic acid (AA), a membrane-abundant polyunsaturated fatty acid, is primarily liberated from membrane phospholipids by phospholipase A (PLA), and is subsequently metabolized into bioactive eicosanoids invo...
PURPOSE: Arachidonic acid (AA), a membrane-abundant polyunsaturated fatty acid, is primarily liberated from membrane phospholipids by phospholipase A (PLA), and is subsequently metabolized into bioactive eicosanoids involved in vascular tone and inflammation. With lipidomics advances, AA metabolism's multifaceted roles in the tumor microenvironment (TME) have emerged, and it is recognized as a key driver and potential therapeutic axis in lung adenocarcinoma (LUAD). We utilized spatial transcriptomics sequencing (ST-seq) and LUAD-associated single-cell RNA sequencing (scRNA-seq) to explore crucial AA-related biomarkers in LUAD. PATIENTS AND METHODS: ScRNA-seq and ST-seq data underwent quality control, integration, clustering, and annotation. Cellular communication analysis explored TME cell/regional regulatory links. Differential cell populations were identified between primary tumor and normal groups; key cells were selected via enrichment pathways and communication patterns. Biomarkers were chosen through differential expression analysis and protein-protein interaction (PPI) network, followed by enrichment analysis, molecular/drug network construction, key cell re-clustering, and pseudotime analysis. RESULTS: Twelve cell types were identified in scRNA-seq, with T cells and epithelial cells among the top three. ST-seq revealed LUAD tissues comprise cancer, lymph, normal epithelium, and stroma regions. T cells and epithelial cells had extensive intercellular connections, designated as key cells. PTGS2, TBXAS1, AKR1C3, and HPGD were selected as biomarkers via PPI network. Re-clustering and pseudotime analysis showed most LUAD epithelial cells and T cells were terminally differentiated; PTGS2 and HPGD expression rose then declined in the middle-late stages of epithelial cell subpopulation differentiation. CONCLUSION: In this study, we observed the crucial functions of T cells and epithelial cells as well as AA-related biomarkers PTGS2, TBXAS1, AKR1C3, and HPGD in LUAD. These findings provide mechanistic context and suggest testable biomarkers for future translational studies.
A novel ELF4 gene variant disrupts T and NK cell function in a patient with immune thrombocytopenia (ITP).
Kendirli PK, Erdem Ş, Kısaarslan AP … +7 more , Gök V, Kayhan E, Özcan A, Dogan ME, Klein C, Ünal E, Eken A
Inflamm Res · 2026 May · PMID 42151449 · Full text
OBJECTIVE AND DESIGN: In this report, we identified a novel hemizygous ELF4 variant (c.1822G > C; p.Gly608Arg) in an adolescent male with chronic immune thrombocytopenia (ITP) and performed functional immunologic charact...
OBJECTIVE AND DESIGN: In this report, we identified a novel hemizygous ELF4 variant (c.1822G > C; p.Gly608Arg) in an adolescent male with chronic immune thrombocytopenia (ITP) and performed functional immunologic characterization. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) of the patient and age-matched controls were characterized by flow cytometry with respect to T cell phenotype, activation, proliferation and NK cell cytotoxicity. RESULTS: The p.Gly608Arg substitution affects a highly conserved residue in the C-terminal regulatory domain of ELF4 and is predicted to be damaging. Immunophenotyping showed an expanded CD8 T-cell compartment, an inverted CD4/CD8 ratio, reduced naïve T-cell populations, and accelerated acquisition of memory-like phenotypes upon activation. Both CD4 and CD8 T cells displayed increased proliferation following TCR stimulation, consistent with impaired ELF4-dependent regulation of effector T-cell expansion. NK cells exhibited reduced granzyme B and perforin expression and markedly diminished cytotoxicity against K562 targets, indicating defects in maturation and effector function. CONCLUSIONS: These findings suggest that the identified ELF4 variant is associated with combined T- and NK-cell dysfunction. This case expands the clinical spectrum of Deficiency in ELF4, X-linked and underscores the relevance of evaluating ELF4 mutations in patients with unexplained cytopenias accompanied by dysregulated lymphocyte activation and impaired cytotoxic responses.
Multidimensional dissection of shared genetic susceptibility in ulcerative colitis and colorectal cancer: novel insights from integrative single-cell and multi-omics analysis.
Zhu F, Yao X, Liu D … +13 more , Wang S, Huang X, Zhou J, Wang S, Tang S, Lai D, Yang S, Meng X, Zhang X, Zhu Z, Lu X, Zhang T, Xu R
Inflamm Res · 2026 May · PMID 42113310 · Full text
BACKGROUND: Ulcerative colitis (UC) patients carry a 2.5-fold increased risk of colorectal cancer (CRC), yet the shared multi-scale genetic architecture remains poorly understood. We constructed an integrative framework...
BACKGROUND: Ulcerative colitis (UC) patients carry a 2.5-fold increased risk of colorectal cancer (CRC), yet the shared multi-scale genetic architecture remains poorly understood. We constructed an integrative framework across tissue, cellular, and variant levels to systematically dissect the pathogenic evolution of this comorbidity across spatiotemporal dimensions. METHODS: We integrated GWAS data from 100,204 CRC cases and 12,160 UC patients with tissue-specific MAGMA enrichment, embryonic spatial mapping (gsMap), and multidimensional single-cell prioritization (ECLIPSER, CELLECT, scDRS). We further resolved cell-specific co-expression patterns using hdWGCNA and identified high-confidence causal variants and genes through Bayesian fine-mapping (eCAVIAR, fastenloc) and Open4Gene analysis. RESULTS: Genetic susceptibility for both diseases was significantly enriched in the terminal ileum and transverse colon, anchored to E16.5 embryonic gut programs. CD4 + T cells emerged as the core immune hub in UC, exhibiting profound immunometabolic polarization (Th17/IL-17 axis and Warburg effect), while progenitors were identified as the primary cellular origin for CRC malignancy. Pathological progression was characterized by a transition from chronic inflammatory stress toward p53-mediated genomic instability, epithelial-mesenchymal transition (EMT), and vascular remodeling. We prioritized Tier 1 candidate genes-ARPC5, PTGER4, CIB1, PREX1, and S100A10-as key mediators of the comorbidity association between inflammation and cancer. CONCLUSIONS: These findings partially support a "genetic programming-microenvironment triggering" hypothesis, where regional vulnerabilities established by embryonic developmental programs are activated by postnatal insults, though its broad applicability warrants caution. This study provides a comprehensive multi-scale molecular framework for understanding UC-CRC comorbidity, offering potential targets for risk stratification and therapeutic intervention.
Multivariable genome-wide analysis elucidates the shared genetic architecture, immunosenescence features, and gut-origin therapeutic targets of ulcerative colitis-associated multisystem inflammation.
Tang S, Yao X, Wang S … +8 more , Zhu F, Zeng W, Lai D, Meng X, Zhang X, Zhu Z, Zhang T, Xu R
Inflamm Res · 2026 May · PMID 42096094 · Full text
BACKGROUND: Over 25% of patients with ulcerative colitis (UC) develop extraintestinal manifestations (EIMs), resulting in significant systemic morbidity. We define the shared genetic foundation of these manifestations as...
BACKGROUND: Over 25% of patients with ulcerative colitis (UC) develop extraintestinal manifestations (EIMs), resulting in significant systemic morbidity. We define the shared genetic foundation of these manifestations as the UC-associated Multisystem Inflammatory Genetic Architecture (UC-MIGA). This study aims to identify shared genomic drivers and actionable immunosenescence therapeutic targets across the UC-EIM spectrum. METHODS: We applied genomic structural equation modeling (SEM) to seven European-ancestry GWAS datasets (UC, deep vein thrombosis, ankylosing spondylitis, primary sclerosing cholangitis, pyoderma gangrenosum, interstitial lung disease, and erythema nodosum) to identify a shared latent genetic factor (F1). Post-SEM analyses included FUMA mapping, SuSIE/FINEMAP fine-mapping, FUSION/FOCUS transcriptome-wide studies, MAGMA enrichment, CELLECT deconvolution, LDSC partitioned heritability, and single-cell eQTL Mendelian randomization (MR). UC exhibited the highest standardized factor loading (0.9801) on F1, justifying its use as a representative proxy for UC-MIGA in downstream analyses. UC-telomere relationships were assessed via tissue-specific eQTL/sQTL enrichment across 49 GTEx tissues, spatial transcriptomics (gsMap), single-cell profiling (GSE214695, GSE163974), hdWGCNA, and colocalization analyses (eCAVIAR, fastENLOC). RESULTS: SEM identified substantial genetic overlap (CFI = 1.0, SRMR = 0.17). Within the UC-MIGA framework, we identified 17,005 SNPs (P ≤ 1 × 10⁻2⁰⁰), 2,622 risk loci, and 152 high-confidence effector genes. Pathways implicated Th17/Treg imbalance and inflammasome signaling. Super-enhancer regions showed exceptional heritability enrichment (80.16%, fold = 4.79, p = 0.0007). MR identified 35 causal immune cell-gene associations. UC-telomere analyses revealed convergence in colon-specific DNA repair-mitochondrial energetics-telomere maintenance pathways, with B cells prioritized as the core cell type. Colocalization identified NKX2-3 and LINC01475 as high-confidence shared candidates. Embryonic intestinal enrichment supported the developmental origins of this systemic axis. CONCLUSION: UC-MIGA represents a genetically coherent architecture driven by super-enhancer-mediated epigenetic dysregulation, Th17/Treg imbalance, and immunosenescence features, including telomere dysfunction and B-cell exhaustion. The 'developmental vulnerability-environmental trigger' model explains the gut-origin inflammatory cascade underlying extraintestinal manifestations, with UC-telomere analysis providing a genomic foundation for systemic therapeutic strategies targeting the inflammation-aging nexus.
Melatonin improves osteogenic differentiation in a high-glucose environment by activating NRF2 to promote autophagy through the regulation of cross-talk between macrophages and bone marrow mesenchymal stem cells.
Zhang J, Zhu L, Zhou J … +8 more , Yu Q, Yang G, Luo C, Meng J, Mao K, Liu J, Mou D, Yang X
Inflamm Res · 2026 May · PMID 42096091 · Publisher ↗
BACKGROUND: Melatonin (MT) can regulate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but its effect on the osteogenic differentiation of BMSCs under high glucose (HG) conditions is unclea...
BACKGROUND: Melatonin (MT) can regulate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but its effect on the osteogenic differentiation of BMSCs under high glucose (HG) conditions is unclear. Therefore, in this study, the effect of MT on the osteogenic differentiation of BMSCs under HG conditions was investigated. METHODS: A mouse model of diabetic osteoporosis (DOP) was induced by the intraperitoneal injection of streptozotocin (STZ), and macrophages or BMSCs were cultured with 25 mM glucose to construct an in vitro cell model. Different doses of MT were used to treat the mice or cells. Genes and proteins were assessed through RT‒qPCR and Western blotting. ALP staining, alizarin red staining, and HE staining were used to assess the osteogenic differentiation of BMSCs and the advancement of DOP in mice. RESULTS: Under normal conditions, MT could increase the expression of osteogenic differentiation-related proteins RUNX2, OCN, and OPN, and enhance differentiation and mineralization levels in BMSCs; however, MT failed to stimulate osteogenic differentiation in BMSCs under HG conditions. Furthermore, regardless of whether under HG conditions, in macrophages, MT suppressed the expression of the M1 phenotype markers CD86, iNOS, and CCR7 while increasing the expression of the M2 phenotype markers CD206, Arg1, and Ym1. Subsequent experiments revealed that under HG conditions, MT indirectly promoted the osteogenic differentiation of BMSCs through the enhancement of the M2 polarization of macrophages; however, MT was unable to directly influence the osteogenic differentiation of BMSCs. Additionally, in mouse experiments, administering high doses of MT effectively mitigated DOP by lowering blood glucose levels, ameliorating pathological damage in femoral tissues, and enhancing collagen accumulation and osteogenic markers expression. From a mechanistic standpoint, MT triggered autophagy by counteracting the suppressive effect of HG on NRF2, thus reducing HG-triggered ROS generation and inflammation in macrophage, promoting the M2 polarization of macrophages, and mitigating the suppressive effect of HG on the osteogenic differentiation of BMSCs. CONCLUSION: Our study indicates that under HG conditions, MT improves osteogenic differentiation by regulating the crosstalk between M2 macrophages and BMSCs.
The role of DAP12 in immune-related inflammatory diseases.
Lu J, Shi L, Jin G … +3 more , Yang Y, Zhu F, Zhou G
Inflamm Res · 2026 May · PMID 42089995 · Publisher ↗
DNAX-activated protein 12 (DAP12) is a key transmembrane adaptor protein containing an immunoreceptor tyrosine-based activation motif. DAP12 associates with a broad spectrum of cell surface receptors, including triggerin...
DNAX-activated protein 12 (DAP12) is a key transmembrane adaptor protein containing an immunoreceptor tyrosine-based activation motif. DAP12 associates with a broad spectrum of cell surface receptors, including triggering receptors expressed on myeloid cells (TREM1 and TREM2), myeloid DAP12-associating lectin-1 (MDL-1), sialic acid-binding immunoglobulin-like lectin 15 (Siglec15), killer cell immunoglobulin-like receptor (KIR), NKG2C/CD94, and NKp44. They form a sophisticated signaling network that precisely regulates cellular activation, differentiation, and the balance between pro-inflammatory and anti-inflammatory responses. DAP12 is predominantly expressed in innate immune cells, including monocytes/macrophages, microglia, osteoclasts, and natural killer (NK) cells, where it governs key processes like cytokine production, cytoskeletal remodeling, and cytotoxic activity. Dysregulation of DAP12 signaling has been implicated in the pathogenesis of multiple immune-related inflammatory diseases, such as multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. In these conditions, DAP12 contributes to either protective or pathological outcomes depending on the receptor complex and microenvironment. This review provides a comprehensive overview of the structural characteristics of DAP12, its interaction with relevant receptors, and its specific functions in various cell types and immune-mediated inflammation.
Commentary: the TSP-1-CD47-integrin α4β1 axis-deciphering pathogenic mechanisms and therapeutic horizons in rheumatoid arthritis.
Guo J, Mai FY, Li XY … +4 more , Liu Y, Liang JR, Li XL, Li CG
Inflamm Res · 2026 May · PMID 42084785 · Full text
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